Interleukin-2 (IL-2) in combination with ex vivo activated and adoptively transferred cells results in response rates of 20% in patients with renal cell cancer and melanoma. Preclinical studies show that cyclophosphamide and adriamycin can synergize with IL-2 to increase tumor responses. Interferon-alfa alone has in vitro anti-proliferative properties and in clinical trials produced response rates of 15-20% in patients with melanoma and renal cell cancer. We administered cyclophosphamide and adriamycin 2 days before IL-2 and the infusion of lymphokine activated killer cells (LAK) in a standard continuous infusion IL-2/LAK regimen. This was followed sequentially by single agent interferon-alfa. Two dose levels of IL-2 were used (3 and 6 mu/m2/d). Overall response rates were 20% in melanoma (8/40) and 20% in renal cell cancer (8/40). The higher IL-2 dose resulted in substantial, dose-limiting pulmonary toxicity when LAK cells were administered. We conclude that the addition of chemotherapy and interferon-alfa to IL-2/LAK did not substantially improve response rates in patients with melanoma and renal cell cancer.